Papillomaviruses are small DNA tumor viruses that induce benign lesions in their vertebrate hosts. Certain papillomaviruses are also thought to be etiologic agents of malignant tumors, as evidenced by the association of specific human papillomavirus genotypes with cervical carcinoma. In these lesions, changes in the regulation of viral replication and viral transcription are thought to play an important role in the transformation by papillomaviruses. The focus of study in this laboratory is in elucidating how papillomaviruses control their gene expression. Studies of bovine papillomavirus type 1 (BPV-1) have led to the identification of the viral E1 and E2 multigene families. These genes encode proteins that modulate viral replication and viral transcription respectively, In this proposal, we have designed experiments to define further the activities of the BPV-1 E1 and E2 gene products. Our studies are directed toward understanding whether viral replication and viral transcription are coordinately regulated, and if so how. Specifically, The effect of the E2 transcription regulatory proteins on viral replication will be investigated. The experiments will attempt to distinguish between effects on replication mediated through modulation of viral E1 replication gene expression versus direct control by E2 proteins over replication initiation. The effect of the E1 replication genes on viral transcription and cellular transformation will also be investigated. The experiments will address the mechanism by which E1 genes affect transcription and transformation and whether this is a consequence of the replication capacity of the E1 genes or the result of direct control over viral promoters by the E1 proteins. A simple model for how replication and transcription might be coordinately regulated is through a direct association between the E1 and E2 proteins. The potential for such an association will be tested; and if true, characterized. Together, these studies should provide a sound basis from which to define the interplay between the E1 replication proteins and the E2 transcription proteins and how disruptions in these genes alter the transforming potential of papillomaviruses.